Clinical Summary

• The phase 3 HBI-8000-303 trial demonstrated a statistically significant improvement in progression-free survival (PFS) with the addition of the oral histone deacetylase (HDAC) inhibitor HBI-8000 to nivolumab in patients with advanced melanoma.
• The combination achieved an objective response rate (ORR) of 42%, including a 14% complete response rate, compared with an ORR of 31% and a 7% complete response rate with nivolumab alone, with particularly favorable PFS outcomes among patients with normal baseline lactate dehydrogenase (LDH) levels.
• Although gastrointestinal, constitutional, and hematologic toxicities were more frequent with HBI-8000, severe nonhematologic adverse events were generally uncommon, and the addition of HBI-8000 did not increase the incidence of adrenal insufficiency compared with nivolumab alone.

Nikhil I. Khushalani, MD, senior member and vice chair of the Department of Cutaneous Oncology at Moffitt Cancer Center in Tampa, Florida, discusses the primary analysis of the phase 3 HBI-8000-303 trial, presented at the 2026 ESMO Congress in Madrid, Spain. The global, randomized study evaluated HBI-8000, an oral selective histone deacetylase (HDAC) inhibitor, plus nivolumab versus placebo plus nivolumab in patients with advanced melanoma who had not previously received anti-PD-1 therapy for metastatic disease. At a median follow-up of 37 months, the combination significantly improved median progression-free survival (11.7 vs 7.4 months; HR, 0.73) and achieved a higher objective response rate (42% vs 31%), including complete responses in 14% versus 7% of patients. Patients with normal baseline lactate dehydrogenase (LDH) levels appeared to derive particularly substantial benefit, with median PFS of 20 months versus 7.4 months. Overall survival data remain immature.

Khushalani also discusses the safety profile of HBI-8000 plus nivolumab, including gastrointestinal adverse events, fatigue, asthenia, decreased appetite, and hematologic toxicities consistent with HDAC inhibition. Approximately 37% of patients receiving HBI-8000 required dose attenuation, and 14% discontinued study treatment because of treatment-related toxicity. Importantly, the combination did not appear to increase immune-mediated endocrinopathies, with 3 cases of adrenal insufficiency reported in each treatment arm. Khushalani describes the findings as a potentially important advance in advanced melanoma treatment, offering an alternative therapeutic strategy to existing checkpoint inhibitor regimens if regulatory approval is obtained. Further research will be needed to identify predictive biomarkers, establish the combination's overall survival benefit, and evaluate its potential in earlier disease settings.

Transcript

Nikhil I. Khushalani, MD: Hi, my name is Nikhil Khushalani. I'm a cutaneous medical oncologist, a senior member and vice chair in the Department of Cutaneous Oncology at Moffitt Cancer Center in Tampa, Florida.

I'm coming to you from ESMO 2026 in Madrid, Spain, where I presented the results of HBI-8000-303, a global randomized phase 3 trial of HBI-8000, an oral selective HDAC inhibitor, plus nivolumab versus placebo plus nivolumab in patients with advanced melanoma who were naive to anti-PD-1 therapy in the metastatic setting. This was based on the premise of preclinical immunomodulation through epigenetic modification, that HBI-8000 plus an anti-PD-1 agent improved efficacy in a murine model, in a murine syngeneic model. And this led to an earlier phase 1b/2 trial that demonstrated very encouraging efficacy with this combination, which in turn was the impetus for this global phase 3 trial that was run in 15 countries at 123 sites.

These were patients with advanced melanoma who had not previously been treated with an anti-PD-1 agent for their metastatic disease. They could have received this therapy in the adjuvant or the neoadjuvant setting as long as over 6 months had elapsed since their use of anti-PD-1 therapy in that particular setting. Patients were randomized 1:1 to either receiving HBI-8000 orally, 30 mg twice a week, plus once-a-month nivolumab every 28 days at 480 mg versus placebo and the same nivolumab dose. 

The primary endpoint was blinded independent review-assessed progression-free survival, and secondary endpoints were overall response rate, overall survival, and safety. We used 2 stratification factors: baseline serum LDH level as well as tumor PD-L1 status, defined as 1% or more being positive.

In this trial, the demographics were well balanced between both arms. There were fewer females on the HBI-8000 arm numerically and more patients who had M1c or M1d, which is more advanced disease, on the HBI-8000 arm. But outside of that, remaining parameters were fairly well balanced. Approximately a third of patients had an elevated baseline serum LDH level, which is commensurate with what we see for our metastatic patients, and 38% had a BRAF V600 mutation.

The primary endpoint of the trial, median progression-free survival, was significantly improved with the combination of HBI-8000 plus nivolumab at 11.7 months versus 7.4 months for placebo plus nivolumab, and this was at a median follow-up of 37 months. This translated to a hazard ratio of 0.73, a highly statistically significant comparison.

The overall response rate to this combination was 42%, with 14% of patients having a complete response. Seven percent of patients on the placebo plus nivolumab arm had a complete response within an overall response rate of 31%. The overall survival data at this time are not yet mature.

The benefit for this combination was seen across most subgroups, but importantly, patients with a normal LDH appeared to do very well with the combination, with a median PFS of 20 months compared to 7.4 months.

This combination, as anticipated, did have toxicity, and these toxicities were primarily gastrointestinal, such as diarrhea, nausea, vomiting, as well as other constitutional toxicities, such as fatigue, asthenia, and decreased appetite. But in terms of grade 3 and 4 nonhematologic toxicities, these were primarily in single digits.

Approximately a third of patients, 37%, required dose attenuation of HBI-8000 compared to about 18% to 19% on the placebo arm. Overall, 14% of patients discontinued study drug therapy on HBI-8000 secondary to treatment-related toxicity.

With regard to hematologic toxicity, which is again a class effect for HDAC inhibitors, these were clearly far more common on the HBI-8000 arm, but complications from those hematologic toxicities were distinctly uncommon, with just 1 febrile neutropenic episode and no patients requiring myeloid growth factors.

Overall, this was a significant result in the field of melanoma, potentially a new standard of care in addition to the dual checkpoint inhibition that we commonly utilize in this setting. I think very importantly, we did not see an increase in immune-mediated endocrinopathies such as adrenal insufficiency, which is a concern with dual checkpoint inhibition. There were 3 instances of adrenal insufficiency in each arm, so really no different compared to nivolumab alone, and that's important from a patient perspective, because these endocrinopathies typically require lifelong hormone replacement therapy.

We believe there is certainly a role for this if this drug combination were to eventually get approved and receive regulatory approval for commercial use, but also further investigation into biomarkers of response and potentially moving it to earlier stages of disease as well.

Source

Khushalani NI, Pereira RP, Nakakogue TD, et al. Primary analysis of HBI-8000-303: a randomized phase 3 trial of nivolumab plus HBI-8000 or placebo in advanced melanoma. Presented at: ESMO Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA54.